(CNN) -- A third-straight special election defeat in as many months left congressional Republicans reeling Wednesday, seriously concerned about what the November elections have in store for their party.

House Minority Leader John Boehner, R-Ohio, called the defeat a "wakeup call."

"We have to show Americans that we can fix the problems here in Washington and fix the problems that they deal with every day," Boehner said.

Democrat Travis Childers defeated Republican Greg Davis on Tuesday in a Mississippi district that hasn't voted Democratic in more than 15 years, one where George W. Bush defeated John Kerry by 25 points in 2004.

It was a result that even Republicans admit is ominous sign of what could happen in the fall.

"This loss is going to prompt serious introspection by our conference to figure out what went wrong and how to fix it," a Republican leadership aide said. "We have time to do that, and we will if we learn our lessons leading into November. But the next couple of days are not going to be pretty." Watch how Childers' win impacts presidential race »

Democrats control the House by a 236-199 majority. Stacking the deck further against the Republicans is the fact that 26 Republican House members are retiring at the end of their current terms, but only eight Democrats are.

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Stuart Rothenberg, editor of The Rothenberg Report, said the election result exposed clear vulnerabilities for Republicans.

"The idea of Republicans losing a special in Mississippi a couple years ago would have been unthinkable," Rothenberg said. "It shows the problems they are having recruiting candidates, delivering their message, demonizing Democrats and swimming upstream."

Childers, a conservative Democrat and local chancery clerk, defeated Davis, the mayor of Southaven, by 4 percentage points -- a stunning upset by any measure, considering the state's deeply conservative leanings.

Republicans and conservative independent groups pulled out all the stops to defend the seat, pouring upwards of $2 million into the contest and dispatching party heavyweights there in the final days to drum up support, including Vice President Dick Cheney.

The GOP was also desperately trying to avoid a third special-election defeat this year in districts that have long been held by Republicans. In March, Democrat Bill Foster won House Speaker Dennis Hastert's former Illinois seat, and two weeks ago Democrat Don Cazayoux won a Louisiana seat that hadn't voted for a Democrat since the 1970's.

Recognizing the potential for another House seat pickup and the strong tailwind it would provide heading into the fall, Democrats spent a similar amount of money on the race, financing several television ads that questioned Davis' competence and ethics. Read more on the ad controversy

And in a sign of just how nasty the contest became, Democrats also sent out a last-minute mailing suggesting that Davis supported moving a statue of the Ku Klux Klan founder into his city. Davis denied that allegation, though Democrats cited a 2005 New York Times article that suggested he was at least open to the idea

In the end, Democrats say the election result sent a "political thunderbolt across America."

"It is yet another rejection of the House Republican agenda, the Bush administration's misguided policies and John McCain's campaign for a third Bush term," Democratic Congressional Campaign Committee Chairman Chris Van Hollen said. See answers to the question: "Should congressional Republicans start packing?" »

National Republican Congressional Committee Chairman Tom Cole issued a sobering assessment of the race, saying "time is short" for his party to establish a bold agenda that will lead to election victories in the fall.

"When you lose three of these in a row, you have to get beyond campaign tactics and take a long, hard look at whether this is something wrong with your product," he said Wednesday. "I think we have several challenges ahead of us. ... It is evident to me that a large section of the American people does not have confidence in the American people to deal with the issues in front of them."

To that end, the party unveiled a broad "pro-family" agenda for the fall Wednesday.

Democrats have said they view as many as 50 Republican congressional seats up for grabs in November, including several in conservative-leaning districts like the three they have won this year.

National Republican Congressional Committee spokeswoman Julie Shutley called that number "wishful thinking," though she declined to speculate on how many seats the party is in danger of losing.

Shutley also said several freshman Democrats in conservative-leaning districts will face tough races in the fall.

"Those members have been taken votes for two years, votes that are a lot more liberal than what they campaigned on," she said.

"Their tactics failed as far as trying to nationalize the congressional race," he said. "The fact is that they don't have an agenda, they don't have a message, and they are resorting to their old playbook that is now out of date."

Obama said Wednesday that the Mississippi result suggested his name would not scare away voters in conservative districts.

"They were trying to do every trick in the book to try to scare folks in Mississippi," he said. "And it didn't work."

The Republican Party is expected to deploy the Obama strategy in several districts in the fall. The NRCC, the conservative group Freedom Watch and Davis himself spent well over $1 million airing television commercials that linked Childers to Obama.

In one ad, Childers was shown next to Kerry and Obama while the Illinois senator's ranking from the National Journal as the most liberal senator was noted. In another ad paid for by Davis, the Rev. Jeremiah Wright was shown and a narrator chastised Childers for not publicly denouncing the pastor's controversial remarks. That ad also claimed Obama had endorsed Childers. (Childers later said that was not the case.)

But Cole said Wednesday using Barack Obama as a tool in conservative districts could still prove successful.

"I think that's still a useful tool. ... I think reminding people that we have a very liberal and, I think, very inexperienced Democratic nominee, and your opponent is likely to be supporting that individual, is interesting," he said.